Relapse associated with return to drug-seeking and drug-taking behavior after a prolonged period of abstinence represents a serious problem for society. This problem provides a challenge in terms of understanding processes that support relapse and the development of drugs that can attenuate or prevent relapse. Pattern completion functions of the CA3 subregion of the hippocampus have been demonstrated in the context of object based-cue memory tasks, but to date have not been examined in the context of object-based cue-induced relapse to drug-seeking behavior. Furthermore, prior work on visual cue memory functions of the hippocampus have demonstrated disruption of pattern completion following infusion of an opioid antagonist into CA3, providing a potential novel therapeutic target for managing relapse and drug-seeking behavior. This proposal therefore will test the hypothesis that a pattern completion process involving hippocampal CA3 encoding and opiate signaling therein underlies the ability of subsets of object-based cues to evoke relapse to drug seeking/preference. The first aim of this proposal is to use a variant of the conditioned place preference task in which the number of available object-based cues is parametrically adjusted to assess the role of pattern completion in cue-induced relapse to drug-seeking behavior. Furthermore, this aim will provide additional evidence for a pattern completion process and a potential therapeutic target for managing relapse in that it will determine whether systemic administration or local infusion of naloxone into the CA3 region disrupts cue-induced relapse for cocaine. The second aim of this proposal will provide additional evidence for pattern completion in the CA3 during cue- induced relapse to drug seeking. In situ hybridization analysis of Arc mRNA expression will be used to map neural activation in CA3 and the extent to which the same neuronal ensembles are activated by exposure of rats to a subset of drug-associated cues vs. exposure to all cues. Successful completion of these aims should lead to the identification of novel, specific, neural substrates that may be targeted for future behavioral and pharmacological manipulation to better manage drug abuse. PUBLIC HEALTH RELEVANCE: The first goal of this research is to provide evidence for a cue-based pattern completion process mediated by the CA3 subregion of the hippocampus during cue relapse following cocaine exposure. In addition, the results may provide for a potential therapeutic target for managing relapse in drug seeking for cocaine in that it will determine whether systemic administration or local infusion of naloxone into the CA3 region disrupts cue-induced relapse for cocaine. The second goal of this research is to provide additional evidence for pattern completion in the CA3 during cue-induced relapse of drug seeking based on arc mRNA expression in the CA3 region. Successful completion of these goals should lead to the identification of novel, specific, neural substrates that may be targeted for future behavioral and pharmacological manipulation to better manage drug abuse.